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Does Intraesophageal Acid Trigger Bronchial Asthma?
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Does Intraesophageal Acid Trigger Bronchial Asthma? No, But Maybe Yes!
Thethisarticle by Ekstrom and Tibbling published in issue of Chest 995) showed in eight patients
(p with bronchial asthma that intraesophageal perfusion of 0.1 NHCI did not trigger symptoms and/or signs of bronchoconstriction. One could challenge the validity of this observation based on the absence of a doubleblind study design. That is, while the patients were having heartburn, the authors listened for rhonchi and prolonged expiration as well as asked the patients to report any occurrence of respiratory distress. Despite this opportunity for bias, the credibility of their study remains intact. First, intraesophageal acid did not provoke an episode of bronchial asthma that would override the authors' potential bias to demonstrate the lack of provocation. Second, the acid did not provoke symptoms of respiratory distress in the patients while they were having heartburn -a symptom that some had previously associated with their attacks of asthma. We conclude from this study that intraesophageal acid does not trigger symptoms and/or signs of bronchoconstriction. In their article the authors cite data from other studies that support this observation. Our confidence in the validity of the observation that acid failed to trigger symptoms and/or signs of bronchoconstriction is further strengthened by the intellectual honesty of the authors in reporting subclinical laboratory data that would not necessarily support their subjective observation. For instance, they found that the degree of airway sensitivity as determined by the histamine challenge test and measured by changes in the FEV 1 significantly correlated in a direct manner with the propensity for acid to provoke changes in the FEV I' This correlation raises the following question: How can intraesophageal acid fail to trigger symptoms and/or signs of bronchoconstriction, yet in the same eight patients be associated with a subclinical but statistically significant, direct correlation in bronchial reactivity (FEV I) with that measured by the histamine challenge test? An explanation for this paradox may reside in the time segment that the authors studied their patients, ie, day as
VOLUME 96 I NUMBER 5 I NOVEMBER, 1989
opposed to nighttime. It is known that patients with bronchial asthma and gastroesophageal reflux can either become worse or experience adverse pathophysiology at night. 1·3 Thus, it is conceivable that daytime provided a less than ideal segment of the circadian cycle during which to ask the question whether intraesophageal acid triggers clinically relevant bronchial asthma. If this hypothesis is true, one would expect to find evidence that physiologic events and/or pathophysiology of the two disorders could interrelate at night to adversely affect each other. That evidence exists. For instance, during REM sleep there are rapid changes in autonomic nervous system activity that affect airway smooth muscle tone! and might provoke bronchospasm if potentiated by the effect of acid on the esophagobronchial reflex . This possible potentiation is relevant , especially since increased bronchial responsiveness to histamine and methacholine have been demonstrated more than 1 h after esophageal acid stimulation.v" Alternatively, the effect of sleep on the pathophysiology of gastroesophageal reflux could adversely affect bronchial reactivity by the esophagobronchial reflex. For instance, both recumbency? and sleepv" can prolong the esophageal acid clearance time, increasing the acid mucosal contact time. This prolonged contact could further stimulate the esophagobronchial reflex, especially since proteolytic enzymes such as pepsin in the acid refluxate can cause a "leaky" mucosal barrier that would facilitate [H] + ion back-diffusion.'? That nocturnal acid gastroesopageal reflux may trigger asthmatic attacks is a relevant clinical concern, especially since intraesophageal acid perfusion at night in asthmatic children with an acid-sensitive esophagus causes symptoms and signs of bronchoconstriction. II Hence, the segment of the circadian cycle during which the authors perfused the acid, ie, day rather than the nighttime may explain why acid failed to trigger symptoms and/or signs of bronchoconstriction, yet still subclinically correlated directly with bronchial hyperreactivity as determined by the histamine challenge test. A two-step procedure similar to that used by the authors seems in order to depict those patients whose asthma may be triggered by gastroesophageal reflux. First, one would want to demonstrate the presence of CHEST I 96 I 5 I NOVEMBER,1989
963
acid gastroesophageal reflux, especially that which occurs at night and has a long clearance time. This reflux pattern not only represents a risk factor for esophagitisv':" as well as symptoms and signs of pulmonary aspiration.P:" but also provides the prolonged acid mucosal contact that may stimulate the esophagobronchial reflex to increase bronchial reactivity. Second, following pH monitoring one could demonstrate the presence or absence of acid-induced symptoms and/or signs of bronchoconstriction. This demonstration can be accomplished by using a combination of intraesophageal acid perfusion and pulmonary function test(s) that determine increased bronchial reactivity. In conclusion, while Ekstrom and Tibbling showed in eight awake asthmatic patients that intraesophageal acid failed to trigger clinically apparent bronchospasm, other aspects of their data did not preclude an important association between these two factors. It is conceivable that processes during the sleep period could modulate the effect of acid gastroesophageal reflux on increased bronchial reactivity. Launence F. Johnson, M.D.;* Bethesda, MD Krishnan R. Rajagopal, M.D., F.C.C.ft Washington, DC *Digestive and Pulmonary Disease Divisions, Department of Medicine, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences; and tWalter Reed Army Medical Center. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official policy or as reflecting the views of the Department of the Army or the Department of Defense. REFERENCES
1 Barnes ~ FitzGerald G, Brown M, Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Eng! J Med 1980; 303:263-67 2 DeMeesterTR, Johnson LF, Guy GJ, Toscano MS, Skinner DB. Pattern of gastroesophageal reflux in health and disease. Ann Surg 1976; 184:459-70 3 Johnson LF, DeMeester TR, Haggitt RC. Esophageal epithelial response to gastroesophageal reflux, a quantitative study. Am J Dig Dis 1978; 23:498-509 4 Sullivan CE, Zamel N, Kozar LF, Murphy E, Phillipson EA. Regulation of airway smooth muscle tone in sleeping dogs. Am Rev Respir Dis 1979; 119:87-99 5 Wilson NM, Charette L, Thomson A, Silverman M. Gastroesophageal reflux and childhood asthma: the acid test. Thorax 1985; 40:592-97 6 Herve ~ Denjean A, Jian R, Simonneau G, Duroux E Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986-89 7 Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid foam tablets on gastroesophageal reflux. Dig Dis Sci 1981; 26:673-80 8 Orr WC, Robinson MG, Johnson LF. Acid clearing during sleep in patients with esophagitis and controls. Dig Dis Sci 1981; 26:423-27 9 Orr WC, Johnson LF, Robinson MG. The effect of sleep on swallowing, esophageal peristalsis, acid sensitivity and clearance 964
time. Gastroenterology 1984; 86:814-19 10 Lillemoe KD, Johnson LF, Harmon JW Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982; 92:276-84 11 Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clio Immunoll983; 72:393-98 12 Shay SS, Eggli D, McDonald C, Johnson LF. Gastric emptying of solid food in patients with gastroesophageal reftux. Gastroenteroll987; 92:459-65 13 Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality and results of surgical therapy Surgery 1979; 86:110-19 14 Chernow B, Johnson LF, Janowitz ~ Castell DO. Pulmonary aspiration as a consequence of gastroesophageal reflux-a diagnostic approach. Dig Dis Sci 1979; 24:839-44
Baseline Airway caliber A Confounder in Interpreting Bronchoconstrlctlon and Bronchodllatation In this issue of Chest (p 984), Gross and colleagues report that the absolute amount of bronchodilatation produced by an inhaled anticholinergic agent is inversely related to the initial FEV1 value. Stated simply patients who have more airway obstruction showed a larger improvement expressed as change in FEV1 percent predicted following inhalation of an anticholinergic. Since anticholinergic bronchodilators act by interfering with acetylcholine action at postganglionic muscarinic receptors, these investigators reasonably concluded that the results suggested that the more severely obstructed patients had greater cholinergic tone. Although this conclusion is reasonable and a possible explanation of their results, there are alternative interpretations. The increase in maximal expiratory How produced by an inhaled bronchodilator is an indirect estimate of the increase in luminal diameter produced by the bronchodilator, and this is in turn an indirect estimate of the degree of smooth muscle relaxation produced by the drug. Further, the amount of relaxation is only an indirect estimate of the intensity of the initial stimulation of the smooth muscle. The degree of airway dilatation produced by a given amount of bronchial smooth muscle lengthening following relaxation will be influenced by the airway wall thickness in the same way that airway wall thickness determines the amount of airway narrowing produced by a given amount of smooth muscle shortening. 1 A 20 percent lengthening of muscle would produce a 55 percent decrease in resistance to airflow through an airway in which the wall thickness made up 20 percent of the airway wall area internal to the smooth muscle layer. The same 20 percent lengthening would produce a 70 Editorials
Does Intraesophageal Acid Trigger Bronchial Asthma? No, But Maybe Yes!
Thethisarticle by Ekstrom and Tibbling published in issue of Chest 995) showed in eight patients
(p with bronchial asthma that intraesophageal perfusion of 0.1 NHCI did not trigger symptoms and/or signs of bronchoconstriction. One could challenge the validity of this observation based on the absence of a doubleblind study design. That is, while the patients were having heartburn, the authors listened for rhonchi and prolonged expiration as well as asked the patients to report any occurrence of respiratory distress. Despite this opportunity for bias, the credibility of their study remains intact. First, intraesophageal acid did not provoke an episode of bronchial asthma that would override the authors' potential bias to demonstrate the lack of provocation. Second, the acid did not provoke symptoms of respiratory distress in the patients while they were having heartburn -a symptom that some had previously associated with their attacks of asthma. We conclude from this study that intraesophageal acid does not trigger symptoms and/or signs of bronchoconstriction. In their article the authors cite data from other studies that support this observation. Our confidence in the validity of the observation that acid failed to trigger symptoms and/or signs of bronchoconstriction is further strengthened by the intellectual honesty of the authors in reporting subclinical laboratory data that would not necessarily support their subjective observation. For instance, they found that the degree of airway sensitivity as determined by the histamine challenge test and measured by changes in the FEV 1 significantly correlated in a direct manner with the propensity for acid to provoke changes in the FEV I' This correlation raises the following question: How can intraesophageal acid fail to trigger symptoms and/or signs of bronchoconstriction, yet in the same eight patients be associated with a subclinical but statistically significant, direct correlation in bronchial reactivity (FEV I) with that measured by the histamine challenge test? An explanation for this paradox may reside in the time segment that the authors studied their patients, ie, day as
VOLUME 96 I NUMBER 5 I NOVEMBER, 1989
opposed to nighttime. It is known that patients with bronchial asthma and gastroesophageal reflux can either become worse or experience adverse pathophysiology at night. 1·3 Thus, it is conceivable that daytime provided a less than ideal segment of the circadian cycle during which to ask the question whether intraesophageal acid triggers clinically relevant bronchial asthma. If this hypothesis is true, one would expect to find evidence that physiologic events and/or pathophysiology of the two disorders could interrelate at night to adversely affect each other. That evidence exists. For instance, during REM sleep there are rapid changes in autonomic nervous system activity that affect airway smooth muscle tone! and might provoke bronchospasm if potentiated by the effect of acid on the esophagobronchial reflex . This possible potentiation is relevant , especially since increased bronchial responsiveness to histamine and methacholine have been demonstrated more than 1 h after esophageal acid stimulation.v" Alternatively, the effect of sleep on the pathophysiology of gastroesophageal reflux could adversely affect bronchial reactivity by the esophagobronchial reflex. For instance, both recumbency? and sleepv" can prolong the esophageal acid clearance time, increasing the acid mucosal contact time. This prolonged contact could further stimulate the esophagobronchial reflex, especially since proteolytic enzymes such as pepsin in the acid refluxate can cause a "leaky" mucosal barrier that would facilitate [H] + ion back-diffusion.'? That nocturnal acid gastroesopageal reflux may trigger asthmatic attacks is a relevant clinical concern, especially since intraesophageal acid perfusion at night in asthmatic children with an acid-sensitive esophagus causes symptoms and signs of bronchoconstriction. II Hence, the segment of the circadian cycle during which the authors perfused the acid, ie, day rather than the nighttime may explain why acid failed to trigger symptoms and/or signs of bronchoconstriction, yet still subclinically correlated directly with bronchial hyperreactivity as determined by the histamine challenge test. A two-step procedure similar to that used by the authors seems in order to depict those patients whose asthma may be triggered by gastroesophageal reflux. First, one would want to demonstrate the presence of CHEST I 96 I 5 I NOVEMBER,1989
963
acid gastroesophageal reflux, especially that which occurs at night and has a long clearance time. This reflux pattern not only represents a risk factor for esophagitisv':" as well as symptoms and signs of pulmonary aspiration.P:" but also provides the prolonged acid mucosal contact that may stimulate the esophagobronchial reflex to increase bronchial reactivity. Second, following pH monitoring one could demonstrate the presence or absence of acid-induced symptoms and/or signs of bronchoconstriction. This demonstration can be accomplished by using a combination of intraesophageal acid perfusion and pulmonary function test(s) that determine increased bronchial reactivity. In conclusion, while Ekstrom and Tibbling showed in eight awake asthmatic patients that intraesophageal acid failed to trigger clinically apparent bronchospasm, other aspects of their data did not preclude an important association between these two factors. It is conceivable that processes during the sleep period could modulate the effect of acid gastroesophageal reflux on increased bronchial reactivity. Launence F. Johnson, M.D.;* Bethesda, MD Krishnan R. Rajagopal, M.D., F.C.C.ft Washington, DC *Digestive and Pulmonary Disease Divisions, Department of Medicine, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences; and tWalter Reed Army Medical Center. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official policy or as reflecting the views of the Department of the Army or the Department of Defense. REFERENCES
1 Barnes ~ FitzGerald G, Brown M, Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Eng! J Med 1980; 303:263-67 2 DeMeesterTR, Johnson LF, Guy GJ, Toscano MS, Skinner DB. Pattern of gastroesophageal reflux in health and disease. Ann Surg 1976; 184:459-70 3 Johnson LF, DeMeester TR, Haggitt RC. Esophageal epithelial response to gastroesophageal reflux, a quantitative study. Am J Dig Dis 1978; 23:498-509 4 Sullivan CE, Zamel N, Kozar LF, Murphy E, Phillipson EA. Regulation of airway smooth muscle tone in sleeping dogs. Am Rev Respir Dis 1979; 119:87-99 5 Wilson NM, Charette L, Thomson A, Silverman M. Gastroesophageal reflux and childhood asthma: the acid test. Thorax 1985; 40:592-97 6 Herve ~ Denjean A, Jian R, Simonneau G, Duroux E Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986-89 7 Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid foam tablets on gastroesophageal reflux. Dig Dis Sci 1981; 26:673-80 8 Orr WC, Robinson MG, Johnson LF. Acid clearing during sleep in patients with esophagitis and controls. Dig Dis Sci 1981; 26:423-27 9 Orr WC, Johnson LF, Robinson MG. The effect of sleep on swallowing, esophageal peristalsis, acid sensitivity and clearance 964
time. Gastroenterology 1984; 86:814-19 10 Lillemoe KD, Johnson LF, Harmon JW Role of the components of the gastroduodenal contents in experimental acid esophagitis. Surgery 1982; 92:276-84 11 Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clio Immunoll983; 72:393-98 12 Shay SS, Eggli D, McDonald C, Johnson LF. Gastric emptying of solid food in patients with gastroesophageal reftux. Gastroenteroll987; 92:459-65 13 Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality and results of surgical therapy Surgery 1979; 86:110-19 14 Chernow B, Johnson LF, Janowitz ~ Castell DO. Pulmonary aspiration as a consequence of gastroesophageal reflux-a diagnostic approach. Dig Dis Sci 1979; 24:839-44
Baseline Airway caliber A Confounder in Interpreting Bronchoconstrlctlon and Bronchodllatation In this issue of Chest (p 984), Gross and colleagues report that the absolute amount of bronchodilatation produced by an inhaled anticholinergic agent is inversely related to the initial FEV1 value. Stated simply patients who have more airway obstruction showed a larger improvement expressed as change in FEV1 percent predicted following inhalation of an anticholinergic. Since anticholinergic bronchodilators act by interfering with acetylcholine action at postganglionic muscarinic receptors, these investigators reasonably concluded that the results suggested that the more severely obstructed patients had greater cholinergic tone. Although this conclusion is reasonable and a possible explanation of their results, there are alternative interpretations. The increase in maximal expiratory How produced by an inhaled bronchodilator is an indirect estimate of the increase in luminal diameter produced by the bronchodilator, and this is in turn an indirect estimate of the degree of smooth muscle relaxation produced by the drug. Further, the amount of relaxation is only an indirect estimate of the intensity of the initial stimulation of the smooth muscle. The degree of airway dilatation produced by a given amount of bronchial smooth muscle lengthening following relaxation will be influenced by the airway wall thickness in the same way that airway wall thickness determines the amount of airway narrowing produced by a given amount of smooth muscle shortening. 1 A 20 percent lengthening of muscle would produce a 55 percent decrease in resistance to airflow through an airway in which the wall thickness made up 20 percent of the airway wall area internal to the smooth muscle layer. The same 20 percent lengthening would produce a 70 Editorials